This description focuses mainly on the research described in a recent article published by the inventors (ref. 1.1, Novel suicide ligands of tubulin arrest cancer cells in S-phase. A Davis, J-D Jaing, K M Middleton, Y Wang, I Weisz, Y-H Ling and J G Bekesi, Neoplasia, 1, (6), 498–507, 1999). This description does not include the regimes for synthesizing the core compound which are previously published (ref. 1.2, Anticancer Drug Design 1998) and patent pending (U.S. patent application Ser. No. 09/258,732). The synthesis of iodine acetamido benzoyl ethyl acetate was performed by Imre Weisz, Mount Sinai School of Medicine, N.Y. in August 1998 and is not yet published.
Tubulin and microtubules are important targets for anti-cancer drug development. The first FDA approved anti-cancer tubulin ligands were the vinca-alkaloids which showed therapeutic potential against lymphoma and leukemia (1.3,2). The vinca alkaloids appear to target tubulin and microtubules because of their specificity measured in biochemical assays (3,4) and their affects on microtubule structure in vivo (5,6). Vinca alkaloids are known to depolymerize microtubules in vitro. In contrast, paclitaxel stabilizes microtubules in vitro and in vivo (7,8). Paclitaxel was recently approved for the treatment of ovarian and breast cancer (9,10). The presently accepted mechanism of action is that all anti-tumor tubulin ligands affect dynamic microtubule structures which are most sensitive during mitosis (1.3,11). Subsequent arrest at mitosis induces the apoptotic mechanism to cause cell death. We had been studying small molecular weight compounds that interact with tubulin and require straight forward synthesis with a view to develop them as anti-cancer agents (12,13). This article describes the novel finding that the haloacetamido benzoyl ethyl ester (HAABE) derivatives (FIG. 1a) are acting via tubulin and that these tubulin ligands can uniquely arrest cancer cells in the G1/S cell cycle transition. Optimization of the HAABE series of compounds resulted in the iodine derivative (IAABE) which has a high therapeutic potential for a variety of cancer types.